Interacting molecular loops in the mammalian circadian clock

Science. 2000 May 12;288(5468):1013-9. doi: 10.1126/science.288.5468.1013.

Abstract

We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period and Cryptochrome cycles.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Biological Clocks / genetics
  • Biological Clocks / physiology*
  • CLOCK Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Cell Nucleus / metabolism
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • Cryptochromes
  • Dimerization
  • Drosophila Proteins*
  • Eye Proteins*
  • Feedback
  • Female
  • Flavoproteins / genetics
  • Flavoproteins / metabolism*
  • Gene Expression Regulation
  • In Situ Hybridization
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Models, Biological
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Period Circadian Proteins
  • Photoreceptor Cells, Invertebrate*
  • Protein Biosynthesis
  • RNA / metabolism
  • Receptors, G-Protein-Coupled
  • Suprachiasmatic Nucleus / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Cryptochromes
  • Drosophila Proteins
  • Eye Proteins
  • Flavoproteins
  • Nuclear Proteins
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Receptors, G-Protein-Coupled
  • Trans-Activators
  • Transcription Factors
  • cry protein, Drosophila
  • RNA
  • CLOCK Proteins
  • Clock protein, mouse